The Patient Protection and Affordable Care Act of 2010 (“PPACA”)1 established Offices of Women’s Health within many agencies of the U.S. Department of Health and Human Services (“HHS”), including in the Food and Drug Administration (“FDA”).2 Since the establishment of the FDA’s Offices of Women’s Health, that agency and the National Institutes of Health (“NIH”) Office of Research on Women’s Health, which was established in 1990, have actively sought to advance women’s health by addressing the continuing limited participation of women in clinical trials. PPACA requires the Director of the FDA’s Office of Women’s Health to report on “levels of activity regarding women’s participation in clinical trials and the analysis of data by sex in the testing of drugs, medical devices, and biological products ....”3 This article will review recent efforts by the FDA and NIH to increase representation of women in clinical trials and encourage sex-specific data analysis and reporting.

The Significance of Sex Differences in Clinical Trials

For years, enrollment of women in clinical studies in the United States was limited intentionally due to fear of fetal consequences. A 1977 FDA guidance document recommended excluding women of childbearing age from early dose-ranging studies in light of birth defects and pregnancy complications associated with drugs like Thalidomide.4The 1977 guidance document was broadly interpreted, and years of male-focused studies delayed clinical advancements relevant to women and limited the utility of studies on diseases commonly affecting women.5 In 1992, a General Accounting Office (“GAO”) report determined that women were not adequately included in clinical trials and that data was analyzed for sex differences in fewer than 50 percent of the studies reviewed.6

In 1993, the FDA reversed course, issuing a guideline that promoted enrollment of women in early phase studies and recommended collection and analysis of data on sex differences in drug research.7 In 1998, the FDA issued a regulation requiring new drug application (“NDA”) submissions to include data on trial participation, efficacy, and safety, presented by age, race, and sex, and requiring investigational new drug (“IND”) application data to be tabulated by age, race and sex.8 A regulation finalized in 2000 allowed the FDA to halt IND studies if a sponsor proposes to exclude men or women with reproductive potential from participation in a study because of risk of reproductive or developmental toxicity from the use of an investigational drug.9NIH pursued similar efforts, issuing in 1994, updating in 2000, and amending in 2001 its Policy and Guidelines on the Inclusion of Women and Minorities as Subjects of Clinical Research.10

Despite these regulatory and guidance-based changes, progress on including women in clinical research trials has been slow. A 2001 GAO report concluded that women accounted for 52 percent of total study enrollees for FDA-reviewed drug studies, but participation of women was still below that of men in early phase trials and in cardiovascular disease studies.11 An article published in 2011 by the American Heart Association journal Circulation concluded that there is a dearth of "sex-specific safety and effectiveness data for high-risk cardiovascular devices" and urged the FDA to set forth "more rigorous...requirements for sex-specific data before device approval."12 According to the National Heart Lung and Blood Institute (“NHLBI”), despite cardiovascular disease's role as the leading cause of death for women in the United States, the current overall enrollment of women in cardiovascular disease trials is a paltry 22 percent.13 Moreover, an evaluation of cardiovascular pre-market approval applications published in 2009 “showed persistent underrepresentation of women. Pivotal studies that reported sex enrolled an average of 33.9% women.”14

These studies reflect the insight that clinical studies should attempt to enroll numbers of women that are reflective of the proportion of women suffering from the particular disease or condition.15 The reason is that women may, and do, respond differently to certain pharmaceuticals and medical devices than men. Male-focused studies may fail to adequately address toxicity risks for women. And some medical devices, such as ventricular assist devices and cardiac resynchronization therapy defibrillators, “elicit different responses in women compared to men.”16 Without representative study enrollment, it is unclear whether the research data available reflects the actual safety and efficacy of a device or drug for use in women.17

FDA and NIH Urge Additional Progress

In 2010, the Institute of Medicine (“IOM”) Committee on Women’s Health Research issued a report concerning its examination of “what the research on women’s health has revealed; how that research has been communicated to providers, women, the public and others; and identify[ing] gaps in those areas.”18 The report noted that study design limitations, insufficient recruitment of female participants, and limited reporting of data by sex have "limited possibilities for identifying potentially important sex or gender differences."19 The IOM said: a “lack of taking account of sex and gender differences in the design and analysis of studies, and a lack of reporting on sex and gender differences, has hindered identification of potentially important sex differences and slowed progress in women’s health research and its translation to clinical practice.”20

Recommendations from the IOM Committee included, but were not limited to: (1) increase reporting by the FDA and others of data on efficacy and safety to be reported by sex, including enforcement of the FDA’s regulations (found at 21 C.F.R. Parts 312 and 314) requiring this reporting for drugs, devices, and biologics;21 (2) encourage data safety monitoring boards (“DSMB”s) to track participation, efficacy, and adverse outcomes by sex; and (3) encourage International Committee of Medical Journal Editors (“ICJME”) to establish guidelines concerning separate reporting of clinical trial outcomes’ data for women and men.22 One result of the study was that the IOM hosted a workshop in 2011 to address the recommendation that journals adopt guidelines for the separate reporting of data for women.23 This workshop produced a summary that compiled suggestions for reporting information on sex differences and ways in which “journal policies can influence research reporting.”24 A participant summarized that “[e]ditorial policies that require sex-stratified analysis would affect how studies are designed and conducted, not only how they are reported. The ultimate goal would be a culture change in scientific research that embraces sex as a key variable for analysis.”25

In December 2011 the FDA’s Center for Devices and Radiological Health (“CDRH”) issued a draft guidance document on Evaluation of Sex Differences in Medical Device Clinical Studies.26 The intent of the draft guidance is to improve the quality and consistency of available data regarding the performance of medical devices in both sexes.27 CDRH's guidance document provides direction regarding (1) increasing the percentage of enrollees in device trials who are women, (2) designing studies to allow for the “consideration of sex and associated covariates” such as body size, (3) analyzing study data for sex-linked differences, and (4) “reporting sex-specific information in summaries and labeling for approved devices.”28

The draft guidance document specifically addresses factors that might be barriers to the inclusion of women in clinical trials.29 In order to achieve representative enrollment of women, CDRH recommends that the following background information for the disease or condition which a device is intended to treat or diagnose be included in studies and in documents submitted to the FDA: sex-specific prevalence; sex-specific diagnosis and treatment patterns; proportions of women included in past studies for the target indication; and any known clinically significant sex differences in outcomes related to either safety or effectiveness.30 The draft guidance provides recommendations for new and ongoing Investigational Device Exemption study design, and for completed and postmarket studies.31 CDRH also made recommendations designed to increase subject compliance with follow-up requirements and minimize subject withdrawal from device studies.32 Even though higher numbers of women are now included in studies than ever before, sex-specific analyses are often not published “because of page limitations or journal restrictions.”33

As noted above, on August 30, 2011, the IOM’s Board on Population Health and Public Health Practice hosted a workshop to address the IOM Committee’s recommendation that journals encourage reporting of clinical trial outcomes separately by sex.34 In January 2012, the chief of women’s health research at NIH urged scientific journal editors to require the inclusion of sex-specific data analysis in scientific manuscripts.36 The draft guidance emphasizes reporting “the differences in study outcomes of treatment by sex.”37 It addresses sex-specific statistical analysis and interpretation and reporting in summaries and labeling.38 Reporting enables clinicians to evaluate device options for their patients.

Devices intended for single-sex use would not be expected to address potential sex differences. CDRH requested that interested parties submit their comments by March 19, 2012. Numerous professional groups and media outlets have published summaries of the FDA draft guidance document, but no comments to the FDA were available as this article went to press.31

Conclusion

For well over 20 years, the FDA and NIH have sought to encourage enhanced inclusion of women in clinical research on drugs, and, later, devices. Drugs and devices can affect women (and other subgroups or populations such as ethnic groups) differently from how they affect men ; this issue is no longer up for debate. Although more women have been included in clinical trials over the years, the progress has been insufficient, as the GAO, NHLBI, and several recent studies and reports highlighted above recognize. Spurred by PPACA, the FDA’s new guidance should provide additional assistance to investigators in designing and reporting their clinical trials, and in reaching out to include women in them.

*Opinions expressed herein are attributable to the authors and are not those of St. Jude Children’s Research Hospital.

Pub. L. No. 111-148, § 3509(g), 124 Stat. 536 (codified at 21 U.S.C. 399b). PPACA further recognizes sex differences in research. Specifically, it establishes a nonprofit Patient-Centered Outcomes Research Institute to assist in making informed health decisions by enhancing the evidence on the manner in which health conditions can be “prevented, diagnosed, treated, monitored and managed through research and evidence synthesis that considers variations in patient subpopulations...”Pub. L. No. 11-148, § 6301, 124 Stat. 727-38 (codified at 42 U.S.C. §1320e(b), (c)) The Institute is required to establish a research project agenda, and research pursuant to this section “shall be designed, as appropriate, to take into account the potential for differences in the effectiveness of health care treatments, services, and items as used with various subpopulations,” including women. Id. § (d)(1)(B), (d)(2)(D).

U.S. Department of Health, Education and Welfare, “General Considerations for the Clinical Evaluation of Drugs, HEW (FDA) 77-3040” (Government Printing Office, Washington, September 1977). Thalidomide was used for morning sickness by women outside of the United States in the late 1950s through early 1960s, and results in birth defects such as phocomelia (a congenital absence of a portion of the limbs) and growth deficiencies. The FDA did not approve use of thalidomide until 1998, due to concerns about its safe use of humans and its effect on embryos. Margaret Hamburg, M.D., Commissioner, U.S.F.D.A.”50 Years after Thalidomide: Why Regulation Matters,” FDA Voice Blog (Feb. 7, 2012), available atthis link. See also March of Dimes, Thalidomide, available at http://www.marchofdimes.com/pregnancy/alcohol_thalidomide.html.

U.S. Food and Drug Administration. Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs. 58 FR 39406, July 22, 1993. In this same year, the NIH Revitalization Act of 1993 was enacted; this law directed NIH to establish guidelines for the inclusion of women and minorities in clinical research. PL 103-43 (codified at 42 U.S.C.A. § 289a-2).

U.S. Food and Drug Administration. Draft Guidance for Industry and Food and Drug Administration Staff: Evaluation of Sex Differences in Medical Device Clinical Studies, December 19, 2011, at 7, available at this link ( recommending that investigators “strive to enroll representative proportions of women and men (i.e., consistent with disease prevalence) to improve the quality and consistency of availabe sex-specific data” for the device being studied).

Id. at 12. The Report observed “inadequate enforcement of requirements that representative numbers of women be included in clinical trials and that women’s results be reported.” Id. at 10. Inadequate enforcement of requirements for recruitment and reporting data by sex has limited the opportunity to identify gender differences. Id. at 12.

U.S. Food and Drug Administration. Draft Guidance for Industry and Food and Drug Administration Staff: Evaluation of Sex Differences in Medical Device Clinical Studies, December 19, 2011, available at this link

Id. at 6. Barriers include fear of fetal consequences, possible under-diagnosis of women, investigator perception that it is more expensive to recruit women, study inclusion and exclusion criteria, and family responsibilities of women. Id.

Id. at 8-10. Included in these recommendations are continued access studies, provisions for minimum enrollment of women, communication strategies tailored to women, involvement of community or local health care practitioners, and flexible follow-up scheduling with provision of child care.

Institute of Medicine. Sex-Specific Reporting of Scientific Research - Workshop Summary, January 13, 2012, available at http://www.iom.edu/Reports/2012/Sex-Specific-Reporting-of-Scientific-Research.aspx .

U.S. Food and Drug Administration. Draft Guidance for Industry and Food and Drug Administration Staff: Evaluation of Sex Differences in Medical Device Clinical Studies, December 19, 2011, at 11, available at this link.